It is apparent that successful cancer chemotherapy often involves a combination of antitumor agents at precise dosage schedules. Both in animals and man empirical combination regimens have led to improvement in therapy. The therapeutic synergism observed with certain drug combinations must have a pharmacological and biochemical basis. Knowledge of the underlying pharmacological and biochemical components which produce therapeutic synergism would make the choice of combinations as well as their optimal scheduling a more predictable and rational process. We wish to determine the biochemical and pharmacological basis for therapeutic synergism observed in a rodent tumor system using binary drug combinations involving 6 drugs, adriamycin, cyclophosphamide, 5-fluorouracil, L-phenylalanine mustard, methotrexate and methyl-CCNU, all of which are useful in treating human solid tumors. This work will be carried out with mice bearing L1210 ascites cells and L1210 cells in culture. In our view, studies during combination chemotherapy of physiologic disposition and biochemical action of drugs, duration and recovery of tumor and host sensitive tissues from drug action, and effects of drug scheduling, should enable us to begin to understand the basis for therapeutic synergism during combination cancer chemotherapy. The need for this information, which should lead to predictable and selective antitumor activity during combination chemotherapy of solid tumors is enormous.